Millions of Americans suffer from dementia and other cognitive deficits as a result of Alzheimer's disease (AD), a neurodegenerative disease. Due to its occurrence in the brain, it is difficult to diagnose the condition and to determine its cause without dangerous brain biopsy. Scientists believe that as many as 4.5 million Americans suffer from AD. AD usually begins after age 60 and its risk goes up with age. The cause of AD is unknown and, at present, no cure has been found.
AD can only be definitely confirmed after an autopsy, which prevents early accurate diagnosis and treatment of the condition. Neuropathologically, AD is characterized by the presence of neuritic plaques, neurofibrillary tangles and neuronal loss. See Mann. Mech. Ageing Dev. 1985, 3(1), 213. Doctors can diagnose AD correctly up to 90 percent using several tools to diagnose “probable” AD, namely, (1) questions about the person's general health, past medical problems, and ability to carry out daily activities; (2) tests of memory, problem solving, attention, counting, and language; (3) medical tests, such as tests of blood, urine, or spinal fluid; and (4) brain scans.
Postmortem brain tissues of AD victims show the presence of amyloid cores of neuritic plaques that are composed of amyloid β- (Aβ-) protein being predominantly arranged in beta-pleated sheet configuration. See J. Biol. Chem. 1992, 267(24), 17082; and Proc. Natl. Acad. Sci., USA 1986, 83(2), 503.
Deposition of amyloid β- (Aβ-) protein occurs, however, not only in individuals that have AD, but it also frequent among individuals who are undergoing the aging process. Thus, it is very critical to distinguish the AP production due to the normal aging process or to AD or other dementia-causing diseases such as DLB dementia associated with Louis Body. In the normal aging process, non-compact or diffuse amyloid plaques containing less fibrillar AP are deposited primarily in the brain. In contrast, AD patients have brains that are characterized by an unanatomically widespread process of amyloid deposition and neurite plaque formation containing dense amyloid fibrils.
Clinical tests to determine the onset of AD and its progression are not presently sensitive and several agents are reported as potential PET and SPECT imaging tracers. Some of the developmental research on imaging agents useful for the diagnosis of AD and other related diseases are discussed below.
U.S. Patent Publication Application No. 2006/0018825 A1, assigned to BF Research Institute, hereby incorporated by reference, describes a series of BF compounds or a salt or solvate thereof that can be used as a probe for the imaging and diagnosis of diseases in which amyloid P-protein accumulates. These compounds have high specificity for diffuse plaques and act as early indicators of AD. In addition, they have rapid clearance from the brain.
Okamura et al. (in J. Neurosci. 2004, 24(10), 2535) describes a labeled sterylbenzoxazole derivative compound, 18F-radiolabeled 6-(2-fluoroethoxy)-2-[2-(4-methylaminophenyl)ethenyl]-benzoxazole (BF-168), that demonstrated abundant initial brain uptake (3.9% injected dose/gm at 2 min after injection) and fast clearance (t1/2=24.7 min) after intravenous (iv) administration in normal mice. In addition, autoradiograms of brain sections from APP23 transgenic mice at 180 min after iv injection of 18F-radiolabeled BF-168 showed selective labeling of brain amyloid deposits with little non-specific binding.
More recently, Kudo et al. (in J. Nucl. Med. 2007, 48553) have demonstrated the use of a novel compound, F-18 labeled 2-(2-[2-diethylaminothiazol-5-yl]-ethenyl)-6-(2-[fluoro])ethoxybenzoxazol (eB F-227) as a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.
U.S. Pat. Nos. 6,001,331 and 6,696,039 B2, issued Dec. 14, 1999 and Feb. 24, 2004, respectively, hereby incorporated by reference, describe the use of several radiolabeled benzothiazole compounds for imaging amyloid deposits.
U.S. Pat. Nos. 6,168,776 and 6,133,259, issued Jan. 2, 2001 and Oct. 17, 2000, respectively, hereby incorporated by describe amyloid-binding compounds such as Chrysamine G and their use in identifying AD in vivo and other pathological conditions characterized by amyloidosis.
One promising amyloid imaging agent is an analogue of thioflavin T, also known as the Pittsburgh Compound-B or “PIB compound.” PIB is also known as [N-methyl-(11C)]-2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (or [11C]6-OH-BTA-I). PET imaging with 11C-PIB can discriminate AD from frontotemporal lobar degeneration (FTLD). See J. Med. Chem. 2003, 46(13), 2740; and Neurology 2007, 68, 1205. However, use of a C-11 labeled tracer limits imaging to medical centers with a cyclotron.
It is well known that 2,8-diazaspiro[4,5]decane-1,3-dione (RS-86) derivatives are active and centrally effective muscarinic cholinergic agonists, with analgesic and sedative properties in animals when given orally. In addition, it has been shown that the C-11 radiolabeled version of 2,8-diazaspiro[4,5]decane-1,3-dione can be used as a tracer, though the reported study describes brain distribution results with a very low specific activity. Further, the biodistribution of the C-11 radiolabeled 2,8-diazaspiro[4,5]decane-1,3-dione in rats, as a function of time, showed that the initial brain uptake was about 1.1%, with high concentrations of percent dose per gram in areas rich with muscarinic receptors such as caudate, putamen and thalamus. However, as discussed above with respect to 11C-PIB, the utility of a C-11 labeled tracer is limited to medical centers with a cyclotron.
Accordingly, there is a need to provide compounds and methods for imaging and treating AD and amyloidosis-associated pathological conditions that are easily available and cost effective. There is a continuing need to seek novel imaging tracers that are accurate and used in early detection of AD and other related pathological conditions.